This NIH K08 proposal describes a five-year career development training program in neurodegenerative disease genomics research. Dr. Michael Miller has completed clinical residency in Anatomic Pathology and fellowship in Neuropathology at Brigham and Women?s Hospital (BWH) and Boston Children?s Hospital (BCH) at Harvard Medical School (HMS), and will embark on this research program to train for an independent academic research career to investigate the pathogenesis of neurodegenerative disease. In this training program, Dr. Miller will develop expertise in single cell genomics, next-generation sequencing data analysis, biologic interpretation of non-neoplastic human somatic mutations, and application of genomic approaches toward neurodegenerative disease mechanistic inquiry. His mentor, Dr. Christopher Walsh (a Professor of Neurology at HMS and HHMI Investigator at BCH), is a leader in human neurologic disease genetics and genomics. His laboratory has extensive experience in human genetics, neurologic disease gene mapping, single cell genomics, and analysis of large data sets. Dr. Walsh has established a long track record for mentoring other trainees to successful careers in biomedical research. In addition, Dr. Miller has assembled a group of collaborators with complementary expertise, and an Advisory Committee with extensive experience in mentoring physician-scientists to develop independent research programs. He will supplement this training with didactic courses and presentation of work at international and national meetings. The primary scientific objective of the proposed research plan is to study the role of neuronal somatic mutation in Alzheimer?s disease (AD). Dr. Miller provides pilot data indicating that neurons in AD show substantial genome damage in the form of elevated somatic single nucleotide variants (sSNV) compared to control neurons. The proposal will examine the disease context for this finding, by studying its distribution in the AD brain and relationship to known key events in AD cellular pathophysiology: oxidative stress and Tau misfolding. The central hypothesis of this proposal is that aberrant Tau and oxidative damage drive somatic mutation in AD, constituting a cascade of cellular damage that underlies disease pathogenesis. Single cell whole genome sequencing (scWGS) will be employed to address three independent but related questions about the role of somatic mutation in AD: (1) sSNV burden will be compared in 3 areas of the brain affected at different stages in AD, to assess sSNV relationship to disease pathologic advancement; (2) Somatic mutational signatures will be determined for AD, to identify the proximate causes of sSNV, along with direct testing for a putative candidate in oxidized DNA; and (3) neurons with greater Tau accumulation will be examined for sSNV to assess the relationship between cellular pathologic burden and somatic mutations. These studies will examine a novel pathogenic event in AD etiology, significant for the fields of neurodegenerative disease pathogenesis and genomics.